Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease
Authors: Zahra Shirzadi, Stephanie A. Schultz, Wai-Ying W. Yau, Nelly Joseph-Mathurin, Colleen D. Fitzpatrick, Raina Levin, Kejal Kantarci, Gregory M. Preboske, Clifford R. Jack, Martin R. Farlow, Jason Hassenstab, Mathias Jucker, John C. Morris, Chengjie Xiong, Celeste M. Karch, Allan I. Levey, Brian A. Gordon, Peter R. Schofield, Stephen P. Salloway, Richard J. Perrin, Eric McDade, Johannes Levin, Carlos Cruchaga, Ricardo F. Allegri, Nick C. Fox, Alison Goate, Gregory S. Day, Robert Koeppe, Helena C. Chui, Sarah Berman, Hiroshi Mori, Raquel Sanchez-Valle, Jae-Hong Lee, Pedro Rosa-Neto, Myuri Ruthirakuhan, Che-Yuan Wu, Walter Swardfager, Tammie L. S. Benzinger, Hamid R. Sohrabi, Ralph N. Martins, Randall J. Bateman, Keith A. Johnson, Reisa A. Sperling, Steven M. Greenberg, Aaron P. Schultz, Jasmeer P. Chhatwal, Michael W. Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John C. Morris, Richard J. Perrin, Leslie M. Shaw, Zaven Khachaturian, Maria Carrillo, William Potter, Lisa Barnes, Marie Bernard, Hector González, Carole Ho, John K. Hsiao, Jonathan Jackson, Eliezer Masliah, Donna Masterman, Ozioma Okonkwo, Laurie Ryan, Nina Silverberg, Adam Fleisher, Diana Truran Sacrey, Juliet Fockler, Cat Conti, Dallas Veitch, John Neuhaus, Chengshi Jin, Rachel Nosheny, Miriam Ashford, Derek Flenniken, Adrienne Kormos, Tom Montine, Michael Rafii, Rema Raman, Gustavo Jimenez, Michael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Yuliana Cabrera, Sarah Walter, Garrett Miller, Godfrey Coker, Taylor Clanton, Lindsey Hergesheimer, Stephanie Smith, Olusegun Adegoke, Payam Mahboubi, Shelley Moore, Jeremy Pizzola, Elizabeth Shaffer, Brittany Sloan, Danielle Harvey, Arvin Forghanian-Arani, Bret Borowski, Chad Ward, Christopher Schwarz, David Jones, Jeff Gunter, Kejal Kantarci, Matthew Senjem, Prashanthi Vemuri, Robert Reid, Nick C. Fox, Ian Malone, Paul Thompson, Sophia I. Thomopoulos, Talia M. Nir, Neda Jahanshad, Charles DeCarli, Alexander Knaack, Evan Fletcher, Duygu Tosun-Turgut, Stephanie Rossi Chen, Mark Choe, Karen Crawford, Paul A. Yushkevich, Sandhitsu Das, Robert A. Koeppe, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Erin Franklin, Haley Bernhardt, Lisa Taylor-Reinwald, Magdalena Korecka, Michael Figurski, Scott Neu, Kwangsik Nho, Shannon L. Risacher, Liana G. Apostolova, Li Shen, Tatiana M. Foroud, Kelly Nudelman, Kelley Faber, Kristi Wilmes, Leon Thal, Lisa C. Silbert, Betty Lind, Rachel Crissey, Jeffrey A. Kaye, Raina Carter, Sara Dolen, Joseph Quinn, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Karen Dagerman, Bryan M. Spann, James Brewer, Helen Vanderswag, Jaimie Ziolkowski, Judith L. Heidebrink, Lisa Zbizek-Nulph, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Javier Villaneuva-Meyer, Valory Pavlik, Nathaniel Pacini, Ashley Lamb, Joseph S. Kass, Rachelle S. Doody, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Akiva Mintz, Beau Ances, David Winkfield, Maria Carroll, Georgia Stobbs-Cucchi, Angela Oliver, Mary L. Creech, Mark A. Mintun, Stacy Schneider, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Daniel Marson, Hillel Grossman, Martin A. Goldstein, Jonathan Greenberg, Effie Mitsis, Raj C. Shah, Melissa Lamar, Patricia Samuels, Ranjan Duara, Maria T. Greig-Custo, Rosemarie Rodriguez, Marilyn Albert, Chiadi Onyike, Leonie Farrington, Scott Rudow, Rottislav Brichko, Stephanie Kielb, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Martin Sadowski, Thomas Wisniewski, Melanie Shulman, Arline Faustin, Julia Rao, Karen M. Castro, Anaztasia Ulysse, Shannon Chen, Mohammed O. Sheikh, Jamika Singleton-Garvin, P. Murali Doraiswamy, Jeffrey R. Petrella, Olga James, Terence Z. Wong, Salvador Borges-Neto, Jason H. Karlawish, David A. Wolk, Sanjeev Vaishnavi, Christopher M. Clark, Steven E. Arnold, Charles D. Smith, Gregory A. Jicha, Riham El Khouli, Flavius D. Raslau, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Kim Martin, Nancy Kowalski, Melanie Keltz, Bonnie S. Goldstein, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Gaby Thai, Aimee Pierce, Beatriz Yanez, Elizabeth Sosa, Megan Witbracht, Brendan Kelley, Trung Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Ihab Hajjar, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Daniel H.S. Silverman, Sarah Kremen, Kathleen Tingus, Po H. Lu, George Bartzokis, Ellen Woo, Edmond Teng, Neill R. Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Adam P. Mecca, Susan P. Good, Martha G. MacAvoy, Richard E. Carson, Pradeep Varma, Howard Chertkow, Susan Vaitekunis, Chris Hosein, Sandra Black, Bojana Stefanovic, Chris (Chinthaka) Heyn, Ging-Yuek Robin Hsiung, Ellen Kim, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternak, Irina Rachinsky, Andrew Kertesz, Dick Drost, John Rogers, Ian Grant, Brittanie Muse, Emily Rogalski, Jordan Robson, M.-Marsel Mesulam, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Howard J. Rosen, Bruce L. Miller, David Perry, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Kelly MCCann, Jessica Poe, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, Jerome Yesavage, Joy L. Taylor, Steven Chao, Jaila Coleman, Jessica D. White, Barton Lane, Allyson Rosen, Jared Tinklenberg, Christine M. Belden, Alireza Atri, Kelly A. Clark, Edward Zamrini, Marwan Sabbagh, Ronald Killiany, Robert Stern, Jesse Mez, Neil Kowall, Andrew E. Budson, Thomas O. Obisesan, Oyonumo E. Ntekim, Saba Wolday, Javed I. Khan, Evaristus Nwulia, Sheeba Nadarajah, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Pauline Maillard, John Olichney, Owen Carmichael, Vernice Bates, Horacio Capote, Michelle Rainka, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Allison Perrin, Anna Burke, Douglas W. Scharre, Maria Kataki, Rawan Tarawneh, David Hart, Earl A. Zimmerman, Dzintra Celmins, Delwyn D. Miller, Laura L. Boles Ponto, Karen Ekstam Smith, Hristina Koleva, Hyungsub Shim, Ki Won Nam, Susan K. Schtulz, Jeff D. Williamson, Suzanne Craft, Jo Cleveland, Mia Yang, Kaycee M. Sink, Brian R. Ott, Jonathan Drake, Geoffrey Tremont, Lori A. Daiello, Aaron Ritter, Charles Bernick, Donna Munic, Abigail O'Connell, Jacobo Mintzer, Arthur Wiliams, Joseph Masdeu, Jiong Shi, Angelica Garcia, Paul Newhouse, Steven Potkin, Steven Salloway, Paul Malloy, Stephen Correia, Smita Kittur, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Norman Relkin, Gloria Chiang, Athena Lee, Michael Lin, Lisa Ravdin, Ajay Sood, Kimberly S. Blanchard, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T. Greig, Bonnie Goldstein, Kimberly S. Martin, Christopher Reist, Carl Sadowsky, Walter Martinez, Teresa Villena, Howard Rosen, Gad Marshall, Elaine R. Peskind, Eric C. Petrie, Gail Li, James M. Noble, Jonathan Voglein, Patricio Chrem Mendez, Ezequiel Surace, Snezana Ikonomovic, Neelesh K. Nadkarni, Francisco Lopera, Laura Ramirez, David Aguillon, Yudy Leon, Claudia Ramos, Diana Alzate, Ana Baena, Natalia Londono, Sonia Moreno, Christoph Laske, Elke Kuder-Buletta, Susanne Graber-Sultan, Oliver Preische, Anna Hofmann, Takeshi Ikeuchi, Kensaku Kasuga, Yoshiki Niimi, Kenji Ishii, Michio Senda, Dave Cash, Jee Hoon Roh, Meghan C. Riddle, William Menard, Courtney Bodge, Mustafa Surti, Leonel Tadao Takada, Martin Farlow, VJ Sanchez-Gonzalez, Maribel Orozco-Barajas, Alan E. Renton, Bianca T. Esposito, Celeste M. Karch, Jacob Marsh, Victoria Fernanadez, Gina Jerome, Elizabeth Herries, Jorge Llibre-Guerra, Erik C.B. Johnson, Nicholas T. Seyfried, William S. Brooks, Jacob A Bechara, Erin E. Franklin, Allison Chen, Charles Chen, Shaney Flores, Nancy Hantler, Russ Hornbeck, Steve Jarman, Sarah Keefe, Deborah Koudelis, Parinaz Massoumzadeh, Austin McCullough, Nicole McKay, Joyce Nicklaus, Christine Pulizos, Qing Wang, Sheetal Mishall, Edita Sabaredzovic, Emily Deng, Madison Candela, Hunter Smith, Diana Hobbs, Jalen Scott, Chengjie Xiong, Peter Wang, Xiong Xu, Yan Li, Emily Gremminger, Yinjiao Ma, Ryan Bui, Ruijin Lu, Ralph Martins, Ana Luisa Sosa Ortiz, Alisha Daniels, Laura Courtney, Hiroshi Mori, Charlene Supnet-Bell, PhD (CSB), Jinbin Xu, John Ringman, Nicolas Barthelemy, Jennifer Smith
Journal: JAMA Neurology (2023)

Importance Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). Main Outcome and Measures The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [ P = .001]; ADNI: t = 2.7 [ P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [ P = .002]; ADNI: t = −5.6 [ P &amp;amp;lt; .001]; HABS: t = −2.2 [ P = .03]), greater in older individuals (DIAN: t = 6.8 [ P &amp;amp;lt; .001]; ADNI: t = 9.1 [ P &amp;amp;lt; .001]; HABS: t = 5.4 [ P &amp;amp;lt; .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [ P = .40]; ADNI: t = 0.6 [ P = .50]; HABS: t = 1.8 [ P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P &amp;amp;lt; .001). Conclusions and Relevance The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.